Laser particles-based spatiotemporal and dynamic single-cell multiomics
基于激光粒子的时空和动态单细胞多组学
基本信息
- 批准号:10723601
- 负责人:
- 金额:$ 13.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAreaBar CodesBehavioralBioinformaticsCancer BiologyCell CommunicationCell SeparationCellsCellular biologyColorDNADataDiagnosisDimensionsEffectivenessEnvironmentGeneral HospitalsGenomeGrowthHarvestHealthcareImageIn VitroIndividualInterdisciplinary StudyLasersLifeLocationLymphatic MetastasisMassachusettsMentorshipMetastatic Neoplasm to Lymph NodesMethodsMicroscopeModalityMorphologyMultiomic DataMusOpticsPhenotypePhysiologicalProcessProteomeRNAResolutionSemiconductorsSentinel Lymph NodeShapesSlideSpeedSystems BiologyTechniquesTechnologyTimeTissuesTrainingbiomaterial compatibilitycancer cellcell behaviorcellular imagingepigenomeexperiencein vivoin vivo imaging systeminnovationinsightmalignant breast neoplasmmedical schoolsmultiple omicsnext generationnovelparticleprotein profilingresponsesequencing platformsingle cell analysissingle cell sequencingsingle-cell RNA sequencingspatiotemporaltranscriptometranscriptomics
项目摘要
Project Summary/Abstract
Cells are the basic unit of life. Cells are very dynamic: they change over time and locations, respond to different
environments, and interact with other cells. Over the past decade, single-cell biology has witnessed enormous
growth owing to massive technical advances, such as single-cell sequencing, multi-omics, and spatial omics.
However, obtaining dynamic dimensions of live cells along with their multi-omic information at the single-cell
resolution is currently difficult and certainly not possible on large scales. Here, we propose a novel cell barcoding
technology that has the potential to enable us to collect live information of cells and connect the data to their
detailed omics information. This technology makes use of laser particles (LPs) with unique optical barcodes
for >100,000 channels, each containing a unique DNA barcode. The “dual-barcoding” will allow us to optically
track live cells under a microscope while they are in their natural environment or in culture, acquire their live
information, harvest the cells, acquire the omics information of the same cells by droplet-based next-generation
single-cell sequencing, and then combine the live imaging and omics data at the single cell resolution.
Furthermore, our technique can be upgraded to multi-omics modalities, combining multiple layers of information
from the genome, epigenome, transcriptome, and proteome, together with morphological, locational, functional,
and behavioral data. We will apply the method to study sentinel lymph node (SLN) metastasis of cancer cells in
vivo. The acquired in vivo single-cell imaging and multi-omics data will provide an unprecedented picture of the
cancer cell lymphatic metastasis process. This project has two specific aims. Aim 1 will develop an optical-and-
DNA “dual” barcoding strategy for droplet-based single-cell sequencing. Aim 2 will apply the method to study
breast cancer SLN metastasis in vivo. During the K99 period, the applicant will receive additional training to
expand her experience and shape her independence in the following areas: (1) LPs and optical barcoding, (2)
LP imaging and in vivo mouse imaging, and (3) single-cell sequencing and multi-omics. This proposal is under
the combined mentorship of Dr. Andy Yun (LP technology, optics, and imaging) and Dr. Ralph Weissleder
(cancer biology, in vivo imaging, and system biology), and a team of experts as advisors for single-cell
sequencing and bioinformatics. The interdisciplinary research environment at Massachusetts General Hospital
and Harvard Medical School will significantly facilitate the proposed study. If successful, the proposed study will
offer a new paradigm for “dynamic” single-cell analysis, with unprecedented speed and throughput, enabling
multi-omics modalities for the profiling of proteins, RNAs, and DNAs at the single-cell level, together with cells’
dynamic phenotype information, enable spatial-omics profiling at the 3D resolution without the need for cell
segmentation. This will be a significant step beyond the current single-cell omics strategies that collect only
snapshot data, in vitro or ex-vivo. This new method will transform the way we use imaging and single-cell analysis
and will open enormous applications for scientific discovery, diagnosis, and treatment in healthcare.
项目总结/摘要
细胞是生命的基本单位。细胞是非常动态的:它们随着时间和地点的变化而变化,对不同的
环境,并与其他细胞相互作用。在过去的十年里,单细胞生物学见证了巨大的
由于单细胞测序、多组学和空间组学等技术的巨大进步,
然而,获得活细胞的动态尺寸沿着它们在单细胞处的多组信息,
目前很难解决,而且肯定不可能大规模解决。在这里,我们提出了一种新的细胞条形码,
这项技术有可能使我们能够收集细胞的活体信息,并将数据与它们的
详细的omics信息该技术利用具有独特光学条形码的激光粒子(LP)
对于> 100,000个通道,每个通道包含唯一的DNA条形码。“双条码”将使我们能够光学
在显微镜下跟踪活细胞,当它们处于自然环境或培养中时,
信息,收获细胞,通过基于液滴的下一代
单细胞测序,然后联合收割机以单细胞分辨率组合活体成像和组学数据。
此外,我们的技术可以升级到多组学模式,结合多层信息
从基因组,表观基因组,转录组和蛋白质组,连同形态,位置,功能,
和行为数据。我们将应用该方法研究癌细胞的前哨淋巴结(SLN)转移,
vivo.获得的体内单细胞成像和多组学数据将提供前所未有的图像,
癌细胞淋巴转移过程。该项目有两个具体目标。Aim 1将开发一种光学和
用于基于液滴的单细胞测序的DNA“双重”条形码化策略。目的二将该方法应用于研究
体内乳腺癌SLN转移。在K99期间,申请人将接受额外的培训,
扩大她的经验,并在以下领域塑造她的独立性:(1)LP和光学条形码,(2)
LP成像和体内小鼠成像,和(3)单细胞测序和多组学。该提案在
Andy Yun博士(LP技术,光学和成像)和Ralph Weissleder博士的联合指导
(癌症生物学,体内成像和系统生物学),以及一个专家团队作为单细胞
测序和生物信息学。马萨诸塞州总医院的跨学科研究环境
和哈佛医学院将大大促进拟议的研究。如果成功,拟议的研究将
为“动态”单细胞分析提供了新的范例,具有前所未有的速度和吞吐量,
多组学模式,用于在单细胞水平上分析蛋白质、RNA和DNA,以及细胞的
动态表型信息,能够在3D分辨率下进行空间组学分析,而不需要细胞
细分这将是超越目前单细胞组学策略的重要一步,
体外或离体快照数据。这种新方法将改变我们使用成像和单细胞分析的方式
并将为医疗保健领域的科学发现、诊断和治疗开辟巨大的应用领域。
项目成果
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